Skip to main content

Decrypting signals in the crypt

Final Report Summary - DECRYPT (Decrypting signals in the crypt.)

DECRYPT has allowed our group to strengthen its transition from pure molecular and cellular analysis of bacterial pathogens interactions with the gut mucosal surface to deciphering the molecular and cellular mechanisms of the symbiotic interaction established between the gut microbiota and the same mucosal surface in normal and pathological conditions. Merging these two lines has also been very productive in allowing to decipher some of the « tricks » used by pathogens to subvert the barrier effect of the gut microbiota and efficiently colonize the mucosal surface before proceeding to tissue invasion.
Our major contributions have been as follows:
1- In the context of the pathogenesis of Shigella causing invasion and inflammatory destruction of the human colonic mucosa, we have shown that Shigella sonnei was able to very efficiently colonise the mucosal surface before invading the crypts thanks to its capacity to substitute itself to resident Escherichia coli strains that it eliminate thanks to its expression of a functional Type6 secretory apparatus that is not expressed by Shigella flexneri. We have also unravelled an important mechanism through which Shigella creates an immunosuppressive environment. This is achieved by injecting effector molecules into activated lymphocytes that harden the plasma membrane and alter the formation of the immunological synapse established with antigen-presenting cells. This mechanism called « kiss and run » does not need invasion of T lymphocytes, but simply injection of eytotoxic effectors via the Shigella Type 3 secretory apparatus.
2- Regarding the microbiota in symbiotic interaction with the host intestinal mucosal surface, we have made key contributions illuminating the behavior of symbionts and pathobionts.
- We have been able to proceed to in vitro cultivation of SFB, a clostridial species that is known to program the maturation of the mucosal and possibly systemic immune system after weaning.
- We have deciphered the molecular and cellular mechanisms by which MDP, a building block of the bacterial cell wall (I.e.peptidoglycan) activates the cytosolic innate immune receptor Nod2, thereby leading to stem cell protection against stress such as DNA intercalating agents of X-Rays. MDP acting as Nod2 agonist activates autophagy/mitophagy via Atg16 L1, leading to control of the lethal production of oxygen radicals (ROS). This is the first demonstration for a direct impact of the microbiota on stem cells affecting epithelial regeneration.
- Such mechanisms of cytoprotection may be alter in certain circumstances. This is the case of Streptococcus gallolyticus whose presence in feces is strongly associated with the occurrence of colon cancer. We have demonstrated that the oncogenic environment of the gut, particularly the excess of secondary bile salts that are not properly reabsorbed activates a bacteriocin in S. gallolyticus allowing its growth and intestinal colonization to the expense of commensal enterococci. We have also identified a « crypt-specific core microbiota » (CSCM) in human colonic crypts which is altered in colonic tumors. We are in the process of demonstrating that overgrowth of S. gallolyticus is actually oncogenic. We are on the way to decipher the mechanism of intervention of symbiotic microbiota in colon cancer.
- Last but least, we have deciphered the mechanisms of regulation of lipid absorption by representative bacterial pioneers of the gut microbiota in infants and children. This provides strong support to our translational work on the interface between small intestinal symbiosis and pediatric malnutrition in sub-saharan Africa.
3- We have also deciphered key mechanisms of regulation of the expression of epithelial antimicrobial peptides, particularly the key role of epigenetic modifications and identified molecules from the traditional pharmacopoeia that activate the expression of these molecules.